The Working Group for Civilian Biodefense has identified smallpox as one of the most serious biological agents that could cause disease and deaths in sufficient numbers to cripple a city or region. The National Institute of Allergy and Infectious Disease has targeted research and development of therapeutics, vaccines, adjuvants/immunostimulants, and diagnostics for small pox and other viral diseases. At TSRL, Inc., we have been developing a prodrug strategy for the improvement of antiviral drugs. While recent research in this area has provided a modest increase in the number of drug candidates for treatment of these diseases, many potential antiviral agents are precluded from clinical use due to their extremely low oral bioavailability. Strategies that can improve the oral bioavailability of approved drugs as well as potential drug candidates will facilitate the development of highly effective antiviral agents and reduce undesirable properties such as drug toxicity, poor patient compliance, and high costs associated with current therapy. The prodrug approach recently has been an effective strategy as demonstrated by the recent success of antiviral prodrugs such as adefovir dipivoxil, famciclovir, tenofovir disoproxil, valacyclovir, and valganciclovir. The long-term goal of this project is to improve the oral absorption of poorly absorbed antiviral drugs and to enhance their delivery to specific tissues, thus improving efficacy. The central hypothesis of this proposal is that oral absorption of a poorly absorbed and rapidly metabolized drug that is active against pox viruses (vidarabine) can be improved and new prodrugs can be specifically targeted to the cells of interest. We have become very enthusiastic about prodrugs of vidarabine because of our recent discovery that vidarabine is 3 to 5-fold more active against vaccinia and cow pox viruses than is cidofovir, the only drug currently available to treat pox virus infections. Furthermore, we were able to increase the activity of vidarabine against these viruses approximately 10-fold by combination with an adenosine deaminase inhibitor thereby providing highly significant superiority to cidofovir. The approach used in this project will be the design and synthesis of prodrugs targeted to transporters expressed in human intestine and also targeted to "activation" enzymes that specifically cleave the prodrug moiety to its parent compound. In addition, the design of vidarabine prodrugs will focus on compounds that inhibit the metabolism of vidarabine by adenosine deaminase to further enhance its activity. Recent preliminary studies involving rat duodenal injection of prototype amino acid prodrugs have validated this approach. Plasma levels of vidarabine were >10-fold greater when the prodrug was dosed compared to administration of vidarabine itself. It should be noted that vidarabine is metabolized more extensively in rodents compared to humans thus our proposed use of human cell lines and targeting human transporters is critical. The expertise needed to expand and succeed in these endeavors will be provided by personnel at TSRL, Inc. in collaboration with Dr. John Drach, an expert in the area of antiviral drugs at the University of Michigan, who was a pioneer investigator of vidarabine metabolism and mode of action. [unreadable] [unreadable] The long term objective of this project is to make new oral drug formulations for the treatment of small pox. The expertise needed to succeed in this project will be provided by personnel at TSRL, Inc. in collaboration with Dr. John Drach, an expert in the area of antiviral drugs at the University of Michigan. [unreadable] [unreadable] [unreadable]